Estimates from the U.S. Surveillance, Epidemiology, and End Results registry suggest that melanoma incidence will reach 70,230 cases in 2011, of whom 8790 will die. The rising incidence and predilection for young individuals makes this tumor a leading source of lost productive years in the society.High-dose interferon-α-2b is the only agent approved for adjuvant therapy for melanoma; the improvement in relapse-free survival has been observed across nearly all published studies and meta-analyses. However, toxicity affects compliance, and current research is focusing on biomarkers that may allow selection of patients with greater likelihood of response and exploring new agents either singly or in combination that may improve on the benefit of interferon.In this article, we review the data for the adjuvant therapy for malignant melanoma--focusing on the results obtained with various regimens testing the several formulations of interferon-α2 and the adjuvant studies of vaccines and radiotherapy. Recent advances in the treatment of metastatic disease have established a role for CTLA-4 blockade and BRAF-inhibition, raising hopes that these agents may have a role in the adjuvant setting. At present, several trials investigating combinations of novel agents with existing immunomodulators are underway.